Homo sapiens (human)
For a multicellular organism like the human body coordination of the chemical processes taking place in the various organs of the body is important. Cells must therefore have ways to talk to other cells and exchange signals and they do so by chemicals. There are three different kinds of signals. The first one is autocrine signaling taking place within an individual cell or by interaction with receptors on its surface. The second type is paracrine signaling, with other cells in the neighborhood. The third kind is endocrine signaling: cells release chemical compounds into the blood and the blood carries the chemicals to cells in other organs. Endocrine signaling is carried out by a class of chemicals called hormones which can be divided into two classes. The first class are proteins themselves or they may be peptides or amino acids. The second class consists of hydrophobic molecules called steroids. Since they are hydrophobic they can easily pass through cell membranes and travel in and out of cells. Their function is to act as a switch for control of gene expression. Their targets are proteins called nuclear receptors or nuclear hormone receptors (NHR). NHR consist of two functionally distinct domains, a DNA binding domain (DBD) and a ligand binding domain (LBD). Hormones control the activity of these proteins by binding to the LBD and changing its 3-dimensional structure. This in turn changes the structure of the DBD. Depending on the state of the DBD a gene will then be expressed or not expressed.
The structure here is that of the human androgen receptor LBD together with a small chemical, metribolone (R1881). R1881 is not a steroid itself, but is very similar in its structure to progesterone. The genes that they control are related to sex, in particular the male sex. Malfunctioning of the androgen receptor may cause various diseases and lead to prostate cancer. The LDB shown here is a compactly folded structure consisting mainly of alpha helices. R1881 is buried deeply inside the LDB, consistent with its character. The outsides of proteins are usually hydrophilic (with the exception of membrane proteins) and the interior is often hydrophobic. A hydrophobic molecule like R1881 must therefore feel very much at home in a place like the hydrophobic interior of a protein. NHR are of great interest to the pharmaceutical industry in their search for drugs to cure diseases. The hope is that by being able to control the activity of NHR one is able to control gene expression and thus indirectly control the progression of diseases.
Protein Data Bank (PDB)
Matias, P.M. Donner, P. Coelho, R. Thomaz, M. Peixoto, C. Macedo, S. Otto, N. Joschko, S. Scholz, P. Wegg, A. Basler, S. Schafer, M. Egner, U. Carrondo, M.A.; "Structural evidence for ligand specificity in the binding domain of the human androgen receptor. Implications for pathogenic gene mutations."; J.Biol.Chem.; (2000) 275:26164-26171 PubMed:10840043.
author: Arno Paehler